SUBSTANCE-P AND HISTAMINE INDUCE INTERLEUKIN-6 EXPRESSION IN HUMAN ASTROCYTOMA-CELLS BY A MECHANISM INVOLVING PROTEIN-KINASE-C AND NUCLEAR FACTOR IL-6

Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substa nce P (SP), and histamine. Because IL-6 has been implicated in the eti opathology of different human diseases including multiple myeloma, rhe umatoid arthritis, multiple sclerosis, acquired immunodeficiency syndr ome dementia complex, and Alzheimer's disease, its inhibition may be o f therapeutic interest. A main demand on an effective inhibitor of IL- 6 expression is that it inhibits IL-6 synthesis independently of the i nducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhib ition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1 beta, SP, and histamine. Whereas the antioxidant pyrr olidinedithiocarbamate was only able to inhibit IL-1 beta-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed t hat IL-1 beta-induced IL-6 expression required the transcription facto r nuclear factor-kappa B (NF-kappa B), whereas SP-and histamine-induce d IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein Kinase C or a combinatory inhibiti on of NF-IL-6 and NF-kappa B binding are strategies to effectively sup press IL-6 synthesis. They therefore provide the basis for the develop ment of antiinflammatory drugs used to treat disorders in which IL-6 i s pathogenically involved.